This Program Project supports the San Antonio Family Heart Study (SAFHS), the first comprehensive genetic epidemiological study of atherosclerosis and its correlates in Mexican Americans. Its long-term goal is to detect, characterize, map, and identify new polymorphic genes that influence variation in susceptibility to cardiovascular disease (CVD). More than 1,400 members of 41 extended Mexican American families were recruited without regard to disease status and examined during the first grant period (SAFHS1), 859 family members were recalled during the second grant period (SAFHS2), and 950 were re-examined during the current grant period (SAFHS3). Data from these three examinations includes many quantitative risk factors for CVD, including measures of lipids and lipoproteins, adiposity, insulin and glucose levels, oxidative stress, blood pressure and subclinical measures of atherosclerosis. Genotyping of all family members for >400 markers in a 10 centimorgan map is complete, and many quantitative trait loci (QTLs) for CVD risk factors have been detected and mapped. In the proposed grant period, we begin a new phase that moves beyond QTL localization and is dedicated to the identification and characterization of the genes underlying CVD risk. We propose to follow several of the most promising CVD-risk related QTLs to identify the contributory causal genes. Advanced strategies involving high-density SNP typing, bioinformatic and transcriptional objective prioritization, resequencing, and sophisticated statistical genetic analyses will be employed in Projects 1-3 to achieve these goals. Project 1 will use genetic epidemiologic approaches to follow up findings from the current grant period, including analysis of longitudinal changes in risk factors; and will analyze newly-available data, including genome-wide high density SNP genotypes, and transcriptional profile data, for SAFHS families. Project 2 will pursue gene identification for QTLs related to lipoproteins, oxidative stress, and inflammation. These include QTLs influencing HDL cholesterol levels, oxidized LDL cholesterol levels, and vascular cellular adhesion molecule 1 levels. Project 3 will focus on the identification of obesity related QTLs, specifically QTLx influencing total body fat, resistin levels, and waist circumference. A new project, Project 4, will exploit newly generated genome-wide transcriptional profiles for the rapid identification of novel cis-regulated candidate genes. This project will explore regulatory variation in the proximal promoter elements of 50 cisregulated genes whose expression is correlated with triglyceride or HDL cholesterol levels.